At a Glance

Adenosine deaminase (ADA) deficiency is an autosomal recessive systemic purine metabolic disorder that affects lymphocyte development and function. It is caused by mutations in the ADA gene and, based on their variability, can present in various clinical forms.

The most severe phenotype is the severe combined immunodeficiency (SCID). It is usually evident before 6 months of life. These infants have a failure to thrive leading to severe weight loss and malnutrition. They are often susceptible to life-threatening infections caused by bacteria, viruses, and fungi. Severe thrush, opportunistic infections, and chronic diarrhea are very common. Additional clinical features include elevated liver enzymes, abnormal flaring of the anterior rib ends, prominent costochondral junctions, squared-off scapula, pelvic dysplasia, and neurologic abnormalities (hypotonia, head lag, nystagmus, ataxia). Affected individuals usually have a small underdeveloped thymus.

The less severe "delayed onset" appears in children between 6 and 24 months, whereas "late onset" can affect adults during their second to forth decade. The individuals with delayed and late onset are susceptible to infections, usually in the forms of recurrent otitis, sinusitis, and upper respiratory infections. If not treated, the immune function further deteriorates and signs of chronic pulmonary insufficiency and allergies develop.

The least severe is the "partial ADA deficiency" in which affected children appear immunologically normal.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

To confirm the clinical diagnosis of ADA deficiency, it is first necessary to assess the patient's immune function.

Lymphopenia with an absolute lymphocyte count of less than 2500 cells/mL in an infant definitely requires further testing. Any infant with severe or opportunistic infection should have the full diagnostic assessment. On average, SCID patients have less than 1500 lymphocytes/mL.

Total serum immunoglobulin (Ig) levels of IgG, IgA, IgM, and IgE should be obtained. All immunoglobulin classes are usually decreased, but not always.

Evaluation of lymphocyte function is key for the diagnosis of the disease. This is accomplished by assessment of: antibodies to standard protein vaccines (i.e., diphtheria and tetanus), isohemagglutinins (IgM against blood group antigens), and mitogen stimulation of lymphocytes. Patients with SCID essentially have no antibody formation and have very poor proliferation of lymphocytes.

To differentiate ADA from other types of combined immunodeficiencies, it is necessary to assess the catalytic activity of the ADA enzyme. This can be performed using red cells, blood mononuclear cells, or cultured fibroblasts. Less than 1% of ADA activity or ADA concentrations of 0.3 U/g of hemoglobin is diagnostic of the disease.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Immunoglobulin deficiency might not be recognized until several months after birth. Maternal IgG crosses placenta into baby's circulation, so IgG levels in the newborn and/or young infant can be almost normal. This can affect determination of response to protein vaccines.

The limit of detection of the ADA assay is such that the result of this test should not be used as an independent diagnostic test for ADA deficiency without evidence of immunologic insufficiency. Some healthy individuals can have values below the limit of detection.

Determination of ADA levels is not useful for carrier testing, as carriers may have ADA levels in the normal range.

If the patient has been transfused, ADA activity should not be performed on red cells, as it would not reflect the actual status and may result in normal enzyme levels. If testing cannot be performed prior to red cell transfusion, it is recommended to perform this assay on mononuclear blood cells or cultured fibroblasts.

What Lab Results Are Absolutely Confirmatory?

ADA is the only gene associated with ADA deficiency. A large number of mutations has been identified (missense, nonsense, and frameshift mutations), as well as exon deletions. Molecular testing of the ADA gene can be performed looking for mutations (sequencing) or exon deletions (deletion/duplication analysis).

In T-B-NK- SCID or milder variants showing partial adenosine deaminase deficiency, most patients will have homozygous of compound heterozygous mutations in the ADA gene.

ADA gene sequencing can be performed on both blood or buccal brush samples; gene deletion/duplication requires a blood sample only.

Molecular testing of the ADA gene can confirm the diagnosis of ADA deficiency by testing the affected child or his or her parents. Carrier testing can be performed in siblings or other relatives. Prenatal diagnosis is an option in at-risk pregnancies.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Screening for the most common forms of SCID is now available in some states. This is achieved by identifying T-cell receptor excision circles (TRECs), a normal byproduct of T-cell receptor rearrangement. TRECs are barely detectable in infants with SCID, whereas they are produced in large numbers in healthy neonates.

Specific screening for ADA deficiency is also possible.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

If it is necessary to exclude HIV infection in ADA infants, order only molecular assays, since IgG antibody assays are of no value due to the presence of maternal antibodies in their circulation.